Gamma knife radiosurgery as primary treatment for pineal tumors, a systematic review and pooled analysis of available literature with histological stratification

Background: Pineal region tumors represent extremely rare pathologies, char- acterized by highly heterogeneous histological patterns, whose best management strategy is, to date, controversial. Most of the available evidence for Gamma Knife radiosurgical (GKSR) treatment of PTs arises from multimodal regimens, considering GKSR as an adjuvant modality following surgery or as a salvage treatment at recurrence. The experience with GKSR as primary treatment is limited to a few small case series. We aimed to gather the existing evidence on the topic and analyze single-patient level data to address the ef cacy and safety of primary GKSR when only a biopsy was attempted or biochemical or neuro- imaging diagnosis was available. Methods: We conducted a systematic review of literature searching international databases (Pubmed, Embase, Cochrane, Science Direct) according to the 2020 PRISMA guidelines. The availability of single-patient-level data was among the inclusion criteria. A total of 1054 original works were retrieved. After the exclusion of duplicates and irrelevant works, we included 12 papers in our nal analysis comprising 64 patients. We included 12 additional patients from the authors’ original series (submitted to publication). Results: A total of 76 patients reached the nal analysis. Presumptive diagnoses included intrinsic pineal low-grade (46%), followed by glial low-grade (LGG, 5%), pineoblastoma (4%), germ cell (GCTs, 4%), pineal intermediate differen- tiation (3%), other pineal tumors (3%), glial high-grade (HGG, 2%) and me- ningioma (1%). In 32% of cases, the diagnosis was unclear. Only 57% of cases received histological con rmation. The mean age at treatment was 38.7yo and the mean lesional volume was 5.2 4 cc. All patients received GKSR with a mean mean marginal dose (50% isodose) of 14.7 2.1 Gy. At a median 36mo follow-up, local control was achieved in 84% of cases. Ten patients showed progression within a median time of 19.5 mo. Progression was more common in HGG and GCTs (p¼0.03). Mortality was 13.2%. The median OS was not reached for all included lesions, except high-grade gliomas (8mo). The 3y-OS was 100% for LGG, 90% for the pineal, 60% for GCT, 50% for HHG, and 82% for undetermined tumors. The 3y-PFS was 100% for LGG, 90% for the pi- neal, 32% for GCT, and 0% for HHG. Median PFS was 5mo for HHG and 34mo for GCTs. The radionecrosis rate was 6%, and cystic degeneration was 2%. Ataxia as presenting symptom had a strong predictive role for mortality (OR 104, p¼0.02), while GCTs and HHG histology predicted PD quite well (OR: 13, p¼0.04). Conclusions: These results support the ef cacy and safety of primary GKSR treatment of pineal region tumors. Further studies are needed to validate these results, which highlight once more the importance of the initial presumptive diagnosis for choosing the best therapeutic strategy.